Mitosis is a highly intricate process that requires the precise coordination of several classes of biomolecules such as microtubules, kinesins, and kinases. Such biomolecules effect proper spindle formation and faithful chromosome segregation in proliferating cells; and they are widely viewed as potential targets for anticancer therapeutics because uncontrolled cell proliferation is a hallmark of many cancers. Microtubule inhibitors, such as taxanes and Vinca alkaloids, are used to treat a wide range of cancers because they induce cell death through poisoning the mitotic spindle and inhibiting mitotic progression in proliferating cancer cells. But administration of spindle poisons inevitably elicits severe pathological side effects due in part to the importance of microtubule functions in normal tissues. Agents that selectively inhibit mitotic kinesins (e.g., Eg5/KSP and CENP-E) or mitotic kinases (e.g., Aurora A and B) are currently under investigation in several cancer preclinical and clinical trials, indicating that agents which more specifically inhibit mitosis represent a promising strategy for treating cancer.
Hec1 is an outer layer component of the kinetochore. Hec1 was originally identified as a retinoblastoma (Rb)-interacting protein, and later found to be an essential member of the Ndc80 complex together with Nuf2 and Spc24/25. Initial studies using antibody to neutralize Hec1 activity indicated that Hec1 is critical for chromosome segregation. Subsequent studies using siRNA to suppress Hec1 expression indicated that Hec1 plays a key role in mitotic spindle checkpoint control. Hec1 functions as a specific regulator of several mitotic processes, including chromosome condensation, migration, and spindle assembly checkpoint signaling.
Hec1 overexpression has been observed in a variety of human cancers and is associated with adverse clinical outcomes in primary breast cancers. Overexpression of Hec1 in a mouse model results in spindle checkpoint hyperactivation and tumor formation. The Hec1/Nek2 complex functions primarily during G2 and M phases of the cell cycle. Perturbation of Hec1 or Nek2 function by antagonists (RNAi or antibody) leads to mitotic abnormalities represented by spindle configuration changes and chromosome misalignment. Hec1 and Nek2 are known to interact physically from a yeast two-hybrid assay; and Nek2 phosphorylation of Hec1 S165 in mitosis is critical for Hec1 activity in cells. Taken together, these results suggest that Hec1 is an important target to consider when developing novel therapies for cancer.